Dosage system and method of using same

ABSTRACT

A dosage form is disclosed for delivering a beneficial agent. The dosage form comprises a wall that surrounds and defines an internal space, a composition comprising a beneficial agent, means in the space for aiding in delivering the compositions from the dosage form and, at least one passageway in the wall for delivering the composition from the dosage form.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. patent appln. Ser.No. 06/780,863 filed Sept. 27, 1985, now U.S. Pat. No. 4,612,186, issuedSept. 16, 1986, which Appln. Ser. No. 780/863 is a continuation-in-partof U.S. Pat. Appln Ser. No. 590,778 filed Mar. 19, 1984, now U.S. Pat.No. 4,595,583, issued June 17, 1986, which applications are incorporatedherein by reference and benefit is claimed of their filing dates. Theseapplications are assigned to the ALZA Corp. of Palo Alto, Calif.

FIELD OF THE INVENTION

This invention pertains to both novel and useful dosage system. Moreparticularly, the invention relates to a delivery system comprising awall that surrounds, in at least a part, a reservoir, or an inner hollowbody member housing a thermo-responsive beneficial agent formulation, anexpandable driving member, and a density member. The members comprisingthe delivery system perform in unison for delivering the beneficialagent at a controlled rate to an animal. The animal includes, in onepreferred embodiment, a ruminant environment of use over a prolongedperiod of time. The invention pertains also to a plurality of laminatedstructures used for manufacturing the delivery system, and to methodsfor treating clinical conditions.

BACKGROUND OF THE INVENTION

Animals, such as ruminant animals, which ruminant include cattle, sheep,giraffe, deer, goat, bison and camels, and more particularly cattle andsheep, comprise an important group of animals that require periodicadministration of beneficial agents such as medicines and nutrients. Themedicines and nutrients are administered for the treatment andalleviation of various clinical conditions, and for better health.

Ruminants have a complex three or four compartment stomach. The rumen,the largest of the stomach compartments, serves as an important locationfor receiving and passing medicines and nutrients and the like intoother compartments, including the abomasum and the intestine. Presently,ruminants are treated by repeated administrations of medicines andnutrients and the like at frequent time intervals. This form oftreatment is inconvenient and expensive, and it does not lend itself togood reliable therapy.

Additionally, beneficial agents, medicines and nutrients are orallyadministered in the forms of a bolus to ruminants. However, this form oftherapy, like the repeated dose mode of administration, also does notlend itself to acceptable therapy. That is, ruminants regurgitate whatthey swallow, they chew their cuds, and they spit out conventionalboluses quickly after administration.

There is, therefore, in view of the above presentation, a pressing needfor use in animal therapy including ruminant therapy for a therapeuticdosage system that, after a single administration, efficientlyadministers beneficial agents, medicines and nutrients over a prolongedperiod of time. There is also a pressing need for a therapeutic deliverysystem for prolongedly releasing a beneficial agent, a medicine, or anutrient at a controlled rate in the animal, particularly the rumen, bya delivery system that is easily swalled, for example, by the ruminantand rmeains in the rumen for a long period of time without beingregurgitated or otherwise eliminated from the rumen.

OBJECTS OF THE INVENTION

Accordingly, it is a primary object of this invention to provide both anovel and useful therapeutic dosage system for use in an animalenvironment, which dosage system is indicated for clinical therapy andfulfills a pressing need known to the prior art.

Another and principle object of this invention to provide both a noveland useful therapeutic delivery system for use in ruminant therapy thatfulfills the pressing need to the prior art.

Another object of the invention is to provide a therapeutic deliverysystem for use in animals including ruminants that delivers a medicineor a nutrient at a controlled rate over a prolonged period of time.

Another object of the invention is to provide a therapeutic deliverysystem that can remain in the animal, particularly the rumen of aruminant, for a prolonged period of time.

Another object of the invention is to provide a therapeutic deliverysystem manufactured in the form of a drug dispensing device that isself-contained, self-starting and self-powered in a fluid environment,is easy to make, and can be used for dispensing beneficial agents to awarm-blooded animal.

Yet another object of the invention is to provide a drug delivery systemcomprising an internal capsule arrangement that makes it easier tomanufacture the system at a lesser cost thereby increasing theusefulness of the system for delivering a beneficial agent to animals,particularly for domestic animals.

Yet another object of the invention is to provide a drug delivery systemcomprising a capsule containing in the lumen of the capsule atemperature-sensitive composition, an expandable member and a densifierin optional parallel arrangement, an outer wall comprising at least inpart a semipermeable member surrounding the capsule, and a dispensingpassageway useful for dispensing a beneficial agent to an animal.

Yet another object of the invention is to provide a drug delivery devicecomprising a semipermeable wall that surrounds at least in part aninternal lumen and which delivery device delivers a thermo-sensitivecomposition containing a beneficial agent by the combinedphysical-chemical operations of the composition melting and becomingfluid to semisolid, or the like, with the composition being displacedfrom the device by an expanding member that swells and occupies space inthe area initially occupied by the compartment.

Another object of the invention is to provide a drug delivery systemcomprising a dense member for keeping the delivery system in the rumenover time wherein the delivery system administers a composition that isa complete pharmaceutical dosage regimen for a prolonged period of time,the use of which delivery system requires intervention only for theinitiation of the regimen.

Yet another object of the invention is to provide a drug delivery systemthat can deliver a beneficial drug contained in a thermo-responsive,lipophilic pharmaceutically acceptable carrier that melts in the rumenin the presence of thermal energy absorbed from the rumen environment ofuse into the dispensable composition that is innocuous, therebysubstantially avoiding mammalian tissue irritation and interaction withmammalian protein tissues.

Yet another object of the invention is to provide a drug delivery systemcontaining an eutectic composition comprising at least two componentsand at least one drug, which eutectic composition has a melting pointapproximately the same as the temperature of a warm-blooded animal'srumen, and is dispensed from the delivery system at said temperature.

Yet another object of the invention is to provide a delivery systemcomprising an inner placed capsule housing a thermo-responsivehydrophilic or hydrophobic composition comprising insoluble to solubledrugs, and which thermo-responsive composition in response to energyinput present in the gastrointestinal tract of a ruminant, change itsform and becomes dispensable for operative delivery from the deliverysystem.

Yet another object of the invention is to provide a drug delivery systemfor dispensing a drug to a ruminant, which delivery system comprises aninner capsule body containing a thermosplastic composition, anexpandable component, and a dense member, and which composition includesa beneficial agent that is insoluble in an aqueous environment and canbe housed in the delivery system in a nonaqueous dispensing carrier thatcan be delivered to a ruminant.

Yet another object of this invention is to provide a dosage form foradmitting into an animal for dispensing a beneficial agent forcontrolling endoparasites and ectoparasites.

Yet another object of this invention is to provide a dosage systemmanufactured in the form a dispensing device for the controlled deliveryof trace elements to an animal over a prolonged period of time.

Other objects, features and advantages of the invention will be moreapparent to those skilled in the dispensing art from the followingdetailed description of the specification, taken in conjunction with thedrawings and the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale, but are set forth toillustrate various embodiments of the invention, the drawing figures areas follows:

FIG. 1 is a view of a delivery system designed and manufactured fororally administering a beneficial agent to a warm-blooded animal;

FIG. 2 is an opened view of the delivery system of FIG. 1, through 2--2the vertical length of the delivery system for illustrating thestructure of the delivery system comprising initially an outside wall,an inside wall, a thermo-responsive composition, an expandable memberand a dense member;

FIG. 3 is an opened view through 2--2 of FIG. 1, the vertical length ofthe delivery system, for illustrating another embodiment similar to theembodiment in FIG. 2;

FIG. 4 is an opened view of the delivery system depicting a wallsurrounding a lumen with the delivery system in operation with all theelements of the delivery system acting in concert for the controlleddelivery of a beneficial agent over time;

FIG. 5 is an opened view of a delivery system depicting the system inoperation, as described in respect to FIG. 4;

FIG. 6 is an opened view of a delivery system provided by the inventiondepicting a different internal structural configuration for the elementscomprising the delivery system;

FIG. 7 is an opened view of a delivery system provided with an exteriorwall of varying thickness;

FIG. 8 is an opened view of the delivery system of FIG. 7 in operationdelivering a beneficial agent over time;

FIG. 9 illustrates a cross-section of a laminate provided by theinvention comprising a dense lamina, a heat-responsive lamina and anexpandable lamina;

FIG. 10 illustrates a cross-section of another laminate comprising aheat-responsive lamina, an expandable lamina and a dense lamina;

FIG. 11 illustrates a cross-sections of another lamina provided by theinvention comprising a heat-responsive lamina, a dense lamina and anexpandable lamina;

FIG. 12 depicts the amount of a beneficial agent released over time by asystem provided by the invention;

FIG. 13 depicts the cumulative amount of beneficial agent released by adelivery system over a prolonged period of time, and

FIG. 14 is a graph that depicts the mean steady state plasma level as afunction of dose rate.

In the drawings, and in the specification, like parts in related drawingfigures are identified by like numbers. The terms appearing earlier inthe specification and in the description of the drawing figures, as wellas embodiments thereof, are further described elsewhere in thisdisclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawing figures in detail, which are examples of newand useful therapeutic delivery system for dispensing a beneficialagent, and which examples are not to be construed as limiting, oneexample of a dispenser is depicted in FIG. 1, identified by the numeral10. In FIG. 1, delivery system 10 comprises a body 11 formed of wall 12that surrounds and defines an internal lumen, not seen in FIG. 1.Therapeutic system 10 comprises a passageway 13, indicated by a partialhole, for delivering a beneficial agent from system 10.

FIG. 2 is an opened view of therapeutic dispenser system 10 of FIG. 1.Therapeutic system 10 of FIG. 2 comprises body 11 and wall 12 and atleast one or a plurality of preformed or formed during operation ofdispenser 10 passageway 13. Wall 12 surrounds internal capsule wall 14and internal compartment of lumen 15. Wall 12 is formed in a presentlypreferred embodiment comprises at least in part a semipermeable wallforming composition that is substantially permeable to the passage of anexternal fluid, and it is substantially impermeable to the passage of abeneficial agent and other ingredients contained in system 10. Inanother embodiment semipermeable wall 12 can partly surround the capsuleand the rest of the wall can be of a different composition. Wall 12 isnon-toxic and it maintains its physical and chemical integrity, that is,it does not erode during the dispensing period. System 10 is a preferredembodiment comprising internal capsule wall 14 made in its finalmanufacture as a single unit capsule body member. That is, capsule wall14 cannot easily be separated into part. Further in FIG. 2, capsule wall14 surrounds lumen 15. Lumen 15 contains a thermo-responsive heatsensitive composition 16, identified by wavy lines, containing abeneficial agent 17, represented by dots. Lumen 15 further contains anexpandable driving member 18 that is in layered contact with acontacting surface 19 of thermo-responsive composition 16. Boththermo-responsive composition 16 and expandable member 18 have a shapethat corresponds to the internal shape of capsule wall 14 and lumen 15.Lumen 15 also contains a dense member 20 or densifier that is contactwith thermoresponsive composition 16, which dense member 20 ispositioned in lumen 15 distant from expandable member 18. A passageway13 extends through dense member 20 for delivering beneficial agent 17from system 10. Passageway 13 extends through outer semipermeable wall12 and internal capsule wall 14 for completing communication betweenlumen 15 and the exterior of system 10. Dense member 20 is an importantcomponent of delivery system 10 for keeping system 10 in the rumen of ananimal over a prolonged period of time. In another manufacturingembodiment, the beneficial agent formulation layer 16 and 17, comprisingheat sensitive composition 16 and beneficial agent 17 of system 10 canalternately be heterogeneous in composition versus homogeneous.Beneficial agent formulation layer 16 and 17 can be comprised of asubset of multiple individual beneficial agent formulation layers forproviding pulses of beneficial agent over the delivery duration ofsystem 10. The individual beneficial agent formulation layers can, forexample, be lipophilic and thermo-responsive in nature and are separatedby spacer elements which are, for example, lipopohilic to hydrophilicand thermo-responsive in nature, but contain no beneficial agent.

FIG. 3 depicts another manufacture provided by the invention. FIG. 3 isan opened view of the dispensing system 10 of FIG. 1, and it comprisesbody 11 an exterior wall 12 of uniform thickness, internal wall 14,internal compartment 15, and passageway 13. System 10 further comprisesa thermo-responsive heat composition 16 containing beneficial agent 17.Thermo-responsive heat composition 16 is, in this manufacture,immediately adjacent to passageway 13. Compartment 15 also contains anexpandable driving member 18 in laminar arrangement with thermo-heatresponsive composition 16. Driving member 18 also is in laminararrangement with, and positioned adjacent to dense member 20. Densemember 20 in FIG. 3 is positioned distant from passageway 13.

The delivery system 10 can be manufactured in a variety ofrumen-retentive sizes and shapes for administering system 10 to ruminantanimals. One presently preferred shape is a cylinder-like or capsulelikeshape. For example, for use with sheep, delivery system 10 can embrace acapsule-like shape and have a diameter of about 0.5 inches to 1 inch(1.3 cm to 2.5 cm) and a length of about 0.5 inches to 2.5 inches (1.3cm to 6.6 cm). For use with cattle, system 10 has a diameter of about0.5 inches to 1.5 inches (1.3 cm to 3.8 cm), and a length of about 1inch to 3.5 inches (2.5 cm to 7.8 cm).

Therapeutic delivery system 10 of FIGS. 1, 2 and 3 in operation deliversbeneficial agent 17 to the fluidic environment of use by a combinationof thermodynamic and kinetic integrally performed activities. That is,in operation, heat sensitive composition 16 in response to thetemperature of the rumen absorbs energy, melts and forms a fluidic or asemi-paste like deliverable composition for delivering agent 17 throughpassageway 13. As composition 16 melts, concomitantly external fluid isimbibed through external semipermeable wall 12 by expandable hydrophiliclayer 18 in a tendency towards osmotic equilibrium, as seen in FIG. 4and FIG. 5, to continuously expand and swell layer 18. Layer 18 expands,in a preferred embodiment, while maintaining an intact immiscibleboundary at interface 21 defined by heat-sensitive composition 16 andexpandable layer 18. The expansion and swelling of layer 18 increasesthe volume of layer 18 and simultaneously layer 18 expands incompartment 15, as seen in FIGS. 4 and 5, thereby urging composition 16through passageway 13. Further in operation, as fluid is imbibed intodevice 10, in the embodiment wherein internal wall 14 is formed of athin-walled, water-soluble gelatin capsule that dissolves at a bodytemperature of 37° C., the capsule softens and dissolves leaving system10 with semipermeable wall 12. The dissolved gelatin blends withcomposition 16, and in some instances lubricates the inside surface ofwall 12. Dense member 19 maintains delivery system 10 in the rumenthereby enabling delivery system 10 to deliver beneficial agent 17 at acontrolled rate over a prolonged period of time, usually about 1 day toabout 6 months, or longer.

FIG. 6 is an opened view of delivery system 10 depicting yet a differentinternal laminated arrangement of the members forming system 10. In FIG.6, system 10 comprises heat-sensitive lamina 16 immediately adjacent topassageway 13, expandable laminate 18 positioned distant from passageway13, and also distant from heat-responsive lamina 16, and a dense lamina20 positioned between heat-responsive lamina 16 and expandable lamina18.

FIG. 7 is an opened view of delivery system 10 depicting delivery system10 comprising the internal structure identified previously. In FIG. 7,delivery system 10 is provided with an external semipermeable wall 12 ofvarying thickness. In the embodiment illustrated, wall 12, increases inthickness from the top of delivery system 10 near passageway 13 towardsbottom 9 of delivery system 10. By providing delivery system 10 withsemipermable wall 12 of varying thickness, the invention provides amultiplicity of drug delivery programs and patterns. Delivery system 10,of FIG. 7 in operation, as depicted in FIG. 8 and in the mannerpreviously described, with internal wall 14 of FIG. 8 lubricating theinside surface of wall 12 as accompanied by the outward and upwardexpansion of members 16 and 18.

FIG. 9 is an opened view of a laminated structure corresponding to theinternal arrangment depicted for delivery system 10 of FIG. 2. In FIG.9, the three-layered laminate 22 comprises a dense lamina 20, aheat-responsive lamina 16 and an expandable lamina 18. Dense lamina 20has a passageway 13 therethrough for communicating with lamina 16.Lamina 16 contains beneficial agent 17.

FIG. 10 is a tri-lamina in opened view that depicts the laminatedarrangement used for manufacturing system 10 of FIG. 3. In FIG. 10tri-lamina 22 comprises heat-responsive lamina 16, containing beneficialagent 17 laminated to expandable lamina 18, which later lamina 18 islaminated to dense lamina 20.

FIG. 11 depicts an opened cross-section laminate 22. Laminate 22illustrates the structure of FIG. 6 comprising a dense lamina 20position between and in contacting arrangementtwith a heatresponsivelamina 16 containing agent 17 and an expandable lamina 18.

While FIGS. 1 through 11 illustrate various delivery systems 10 that canbe made according to the invention, it is to be understood these systemsare not to be construed as limiting the invention, as the dispenser cantake other shapes, sizes and forms for delivering beneficial agents tothe biological environment of use. The delivery system can be used inveterinary clinics, farms, zoos, laboratories, on the range, in feedlots and other environments of use.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of this invention, it has now been foundthat internal wall 14 of delivery system 10 can be made as a capsulemember. The capsule member generally is tubular shaped and it has amouth at one end, and at the end distant therefrom it is closed in ahemispherical or dome shaped end. The capsule member serves as a hollowbody having a wall that surrounds and defines an interior compartmentprovided with an opening for establishing communication with theexterior of the capsule and for filling the capsule.

In one embodiment, a capsule is made by dipping a mandrel, such as astainless-steel mandrel, into a batch containing a solution of a capsulewall forming material to coat the mandrel with the material. Then, themandrel is withdrawn, cooled, and dried in a current of air. The capsuleis stripped from the mandrell and trimmed to yield a capsule with aninternal lumen.

The materials used for forming the capsule are the commerciallyavailable materials including gelatin, gelatin having a viscosity of 15to 30 millipoises and a bloom strength up to 150 grams; gelatin having abloom value of 160 to 250; a composition gelatin, glycerine water andtitanium dioxide; a composition comprising gelatin, erythrosin, ironoxide and titanium dioxide; a composition comprising gelatin, glycerine,sorbitol, potassium sorbate and titanium dioxide; a compositioncomprising gelatin, acacia, glycerin and water; water soluble polymersthat permit the transport of water therethrough and can be made intocapsules, and the like.

Representative materials for forming the semipermeable wall 12 includesemipermeable homopolymers, semipermeable copolymers, and the like. Inone embodiment typical materials include cellulose esters, cellulosemonoesters, cellulose diesters, cellulose triesters, cellulose ethers,and cellulose ester-ethers, mixtures thereof, and the like. Thesecellulosic polymers have a degree of substitution, D.S., on theiranhydroglucose unit from greater than 0 up to 3 inclusive. By degree ofsubstitution is meant the average number of hydroxyl groups originallypresent on the anhydroglucose unit that are replaced by a substitutinggroup, or converted into another group. The anhydroglucose unit can bepartially or completely substituted with groups such as acyl, alkanoyl,aroyl, alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkylcarbamate,alkylcarbonate, alkylsulfonate, alkysulfamate, and like semipermeablepolymer forming groups.

The semipermeable materials typically include a member selected from thegroup consisting of cellulose acylate, cellulose diacylate, cellulosetiacylate, cellulose acetate, cellulose diacetate, cellulose triacetate,mono-, di- and tri-cellulose alkanylates, mono-, di- andtri-alkenylates, mono-, di-and tri-aroylates, and the like. Exemplarypolymers including cellulose acetate having a D.S. of 1.8 to 2.3 and anacetyl content of 32 to 39.9%; cellulose diacetate having a D.S. of 1 to2 and an acetyl content of 21 to 35%; cellulose diacetate having a D.S.of 1 to 2 and an acetyl content of 21 to 35%; cellulose triacetatehaving a D.S. of 2 to 3 and an acetyl content of 34 to 44.8%, and thelike. More specific cellulosic polymers include cellulose propionatehaving a D.S. of 1.8 and a propionyl content of 38.5%; cellulose acetatepropionate having an acetyl content of 1.5 to 7% and an acetyl contentof 39 to 42%; cellulose acetate propionate having an acetyl content of2.5 to 3%, an average propionyl content of 39.2 to 45% and a hydroxylcontent of 2.8 to 5.4%; cellulose acetate butyrate having a D. S. of1.8, and acetyl content of 13 to 15%, and a butyryl content of 34 to39%; cellulose acetate butyrate having an acetyl content of 2 to 29.5%,a butyryl content of 17 to 53%, and a hydroxyl content of 0.5 to 4.7%;cellulose triacylates having a D.S. of 2.9 to 3 such as cellulosetrivalerate, cellulose trilaurate, cellulose tripalmitate, celllosetrioctanoate, and cellulose tripropionate; cellulose diesters having aD.S. of 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate,cellulose dioctanoate, cellulose dicarpylate; cellulose propionatemorpholinobutyrate; cellulose acetate butyrate; cellulose acetatephthalate, and the like; mixed cellulose esters such as celluloseacetate valerate, cellulose acetate succinate, cellulose propionatesuccinate, cellulose acetate octanoate, cellulose valerate palmitate,cellulose acetate heptonate, and the like. Semipermeable polymers areknown in U.S. Pat. No. 4,077,407, and they can be made by proceduresdescribed in Encyclopedia of Polymer Science and Technology, Vol. 3, pp325 to 354, 1964, published by Interscience Publishers, Inc., New York.

Additional semipermeable polymer include acetaldehyde dimethyl celluloseacetate; cellulose acetate ethylcarbonate; cellulosedimethylaminoacetate; a cellulose composition comprising celluloseacetate and hydroxypropyl methylcellulose; a composition comprisingcellulose acetate and cellulose acetae butyrate; a cellulose compositioncomprising cellulose acetate butyrate and hydroxypropyl methylcellulose;semipermeable polyamides; semipermeable polyurethanes; semipermeablepolysulfanes; semipermeable sulfonated polystyrenes, cross-linked,selectively semipermeable polymers formed by the coprecipitation of apolyanion and a polycation as disclosed in U.S. Pat. Nos. 3,173,876;3,276,586; 3,541,005; 3,541,006, and 3,546,142; selectivelysemipermeable silicon rubbers; semipermeable polymers as disclosed byLoeb and Sourirajan in U.S. Pat. No. 3,133,132; semipermeablepolystyrene derivatives; semipermeable (polysodium-styrenesulfonate);semipermeable poly(vinylbenzyltrimethyl) ammonium chloride;semipermeable polymer exhibiting a fluid permeability of 10⁻¹ to 10⁻⁷(cc·mil/cm 2 hr·atm) expressed as per atmosphere of hydrostatic orosmotic pressure difference across a semipermeable wall. The polymersare known to the art in U.S. Pat. Nos. 3,845,770, 3,916,899, and4,160,020 and Handbook of Common Polymers, by Scott, J. R. and Roff, W.J. 1971, published by CC Press, Cleveland, Ohio.

Wall 12 also can comprise a flux regulating agent. The flux regulatingagent is a compound added regulating the fluid permeability of fluxthrough the wall 12. The flux regulating agent can be a flux enhancingagent or a flux decreasing agent. The agent can be preselected toincrease or decrease the liquid flux. Agents that produce a markedincrease in permeability to fluid such as water, are often essentiallyhydrophilic, while those that produce a marked decrease to fluids suchas water, are essentially hydrophobic. The amount of regulator in thewall when incorporated therein generally is from about 0.01% to 20% byweight or more. The flux regulator agents in one embodiment thatincrease flux include polyhydric alcohols, polyalkylene glycols,polyalkylenediols, polyesters of alkylene glycols, and the like. Typicalflux enhancers include polyethylene glycol 300, 400, 600, 1500, 4000,6000 and the like; low molecular weight glycols such as polypropyleneglycol, polybutylene glycol and polyamylene glycol: thepolyalkylenediols such as poly(1,3-propanediol), poly(1,4-butanediol),poly(1,6-hexanediol), and the like; aliphatic diols such as 1,3-butyleneglycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol, and thelike; alkylene triols such as glycerine, 1,2,3-butanetriol,1,3,4-hexanetriol, 1,3,6-hexanetriol and the like; ester such asethylene glycol diproprionate, ethylene glycol butyrate, butylene glycoldipropionate, glycerol acetate esters, and the like. Representative fluxdecreasing agents include phthalates substituted with an alkyl, andalkoxy or with both an alkyl and alkoxy group such as diethyl phthalate,dimethoxyethyl phthalate, dimethyl phthalate, and[di(2-ethyl-hexyl)phthalate], aryl phthalates such as triphenylphthalate, and butyl benzyl phthalate; insoluble salts such as calciumsulphate, barium sulphate, calcium phosphate, and the like; insolubleoxides such as titanium oxide; polymers in powder, granule and like formsuch as polystyrene, polymethylmethacrylate, polycarbonate, andpolysulfone; esters such as citric acid esters esterfied with long chainalkyl groups; inert and substantially water impermeable fillers; resinscompatible with cellulose based wall forming materials, and the like.

Other materials that can be used to form the wall 12 for impartingflexibility and elongation properties to the wall, for making the wallless-to-nonbrittle and to render tear strength, include phthalateplasticizers such such as dibenzyl phthalate, dihexyl phthalate, butyloctyl phthalate, straight chain phthalates of six to eleven carbons,di-isononyl phthalate, di-isodecyl phthalate, and the like. Theplasticizers include nonphthalates such as triacetin, dioctyl azelate,epoxidized tallate, tri-isoctyl trimellitate, tri-isononyl trimellitate,sucrose acetate isobutyrate, epoxidized soybean oil, and the like. Theamount of plasticizer in a wall when incorporate therein is about 0.01%to 20% by weight, or higher.

Expandable layer 18 that has a shape that corresponds to the internalshape of capsule wall 14 and compartment 15 is made from a hydrogelcomposition. The hydrogel composition is noncross-linked or optionallycross-linked and it possesses osmotic properties, such as the ability toimbibe an exterior fluid through semipermeable wall 12, and exhibit anosmotic pressure gradient across semipermeable wall 12 against a fluidoutside delivery system 10. The materials used for forming theswellable, expandable inner layer and the plug, are polymeric materialsneat, and polymeric materials blended wtih osmotic agents that interactwith water or a biological fluid, absorb the fluid and swell or expandto an equilibrium state. The polymer exhibits the ability to retain asignificant fraction of imbibed fluid in the polymer molecularstructure. The polymers in a preferred embodiment are gel polymers thatcan swell or expand to a very high degree, usually exhibiting a 2 to 50fold volume increase. The swellable, hydrophilic polymers, also known asosmopolymers can be noncrosslinked or lightly cross-linked. Thecross-links can be covalent or ionic bonds with the polymer possessingthe ability to swell in the presence of fluid, and when cross-linked itwill not dissolved in the fluid. The polymer can be of plant, animal orsynthetic origin. Polymeric materials useful for the present purposeinclude poly(hydroxyalkyl methacrylate) having a molecular weight offrom 5,000 to 5,000,000; poly(vinylpyrrolidone) having a molecularweight of from 10,000 to 360,000; anionic and cationic hydrogels;poly(electrolyte) complexes; poly(vinylalcohol) having a low acetateresidual; a swellable mixture of agar and carboxymethyl cellulose; aswellable composition comprising methyl cellulose mixed with a sparinglycross-linked agar; a water-swellable copolymer proudced by a dispersionof finely divided copolymer of maleic anhydride with styrene, ethylene,propylene, or isobutylene; water swellable polymer of N-vinyl lactams;and the like.

Other gelable, fluid imbibing and retaining polymers useful for formingthe hydrophilic, expandable push member include pectin having amolecular weight ranging from 30,000 to 300,000; polysaccharides such asagar, acacia, karaya, tragacanth, algins and guar; Carbopol®, an acrylicacid polymer, a carboxyvinyl polymer, sometimes referred to ascarboxypolymethylene, a polymer of acrylic acid crosslinked with apolyallyl ether of succrose, as described in U.S. Pat Nos. 2,798,053 and2,909,462 and avilable as Carbopols® 934, 940 and 941, and its saltderivatives; polyacrylamides; water-swellable indene maleic anhydridepolymers; Good-rite® polyacrylic acid having a molecular weight of80,000 to 200,000; Polyox® polyethylene oxide polymers having amolecular weight of 100,000 to 5,000,000; starch graft copolymers;Aqua-Keep® acrylate polymers with water absorability of about 400 timesits original weight; diesters of polyglucan; a mixture of cross-linkedpolyvinyl alcohol and poly(N-vinyl-2-pyrrolidone); zein available asprolamine; poly(ethylene glycol) having a molecular weight of 4,000 to100,000, and the like. In a preferred embodiment, the expandable memberis formed from polymers and polymeric compositions that arethermoformable. Representative polymers possessing hydrophilicproperties are known in U.S. Pat. Nos. 3,865,108; 4,002,173; 4,207,893;4,376,725, and in Handbook of Common Polymers, by Scott and Roff,published by Cleveland Rubber Company, Cleveland, Ohio.

The osmotically effective compound that can be blended homogeneously orheterogeneously with the swellable polymer, to form a push member, arethe osmotically effective solutes that are soluble in fluid imbibed intothe swellable polymer, and exhibit an osmotic pressure gradient acrossthe semipermeable wall against an exterior fluid. Osmotically effectivecompounds are known also as osmagents. Osmotically effective osmagentsuseful for the present purpose include magnesium sulfate, magnesiumchloride, sodium chloride, lithium chloride, potassium sulfate, sodiumsulfate, mannitol, urea, sorbitol, inositol, succrose, glucose, and thelike. The osmotic pressure in atmospheres, ATM, of the osmagentssuitable for the invention will be greater than zero ATM, generally fromeight ATM up to 500 ATM, or higher.

The swellable, expandable polymer, in addition to providing a drivingsource for delivering a beneficial agent from the dispenser 10, furtherserves to function as a supporting matrix for an osmotically effectivesolute. The osmotic solute can be homogeneously or heterogeneouslyblended with the polymer to yield the desired expandable member 18. Thecomposition in a presently preferred embodiment comprises at least onepolymer and at least one osmotic solute. Generally, a composition willcomprise about 20% to 90% by weight of polymer and 80% to 10% by weightof osmotic solute, with a presently preferred composition comprising 35%to 75% by weight of polymer and 65% to 25% by weight of osmotic solute.

The thermo-responsive composition 16, containing agent 17 homogeneouslyor heterogeneously dispersed or dissolved therein, is formed in apresently preferred embodiment of a heat sensitive, hydrophilic orhydrophobic material that exhibits solid-like properties at roomtemperature of 21° C., and within a few centigrade degrees thereof, andexhibits, in a preferred embodiment, a melting point that approximatesmammalian body temperatures of 37° C., and with a few centrigradedegrees thereof. The present invention uses the phrases "melting point","softening point", "pour point", or "liquifies" to indicate thetemperature at which the thermo-responsive composition melts, undergoesdissolution, or forms a paste-like ribbon or dissolves, to form adispensable carrier so it can be used for dispensing agent 17 fromdispenser 10.

The term "thermo-responsive" as used for the purpose of this inventionincludes thermoplastic compositions capable of softening, or becomingdispensable in response to heat and hardening again when cooled. Theterm also includes thermotropic compositions capable of undergoingchange in response to the application of energy in a gradient manner.These are temperature sensitive in their response to the application orwithdrawal of energy. The term "thermo-responsive" as used for thepurpose of this invention in a preferred embodiment denotes thephysical-chemical property of a composition agent carrier to exhibitsolid, or solid-like properties at temperatures up to 31° C., and becomefluid, semisolid, or viscous when disturbed by heat at temperatures from31° C., and usually in the range of 31° C. to 45° C. Thethermo-responsive carrier is heat-sensitive and preferably anhydrous andit has the property of melting, dissolving, undergoing dissolution,softening, or liquifying at the elevated temperature, thereby making itpossible for the dispenser 10 to deliver the thermo-responsive carrierwith the beneficial agent 17 homogeneously or heterogeneously blendedtherein. The thermo-responsive carrier can be lipophilic,, hydrophilicor hydrophobic. Another important property of the carrier is its abilityto maintain the stability of the agent contained therein during storageand during delivery of the agent. Representative thermo-responsivecompositions and their melting points are as follows: cocal meltingpoints are as follows: cocoa butter, 32°-34° C.; cocoa butter plus 2%beeswax, 35°-37°; propylene glycol monostearate and distearate, 32°- 35°C.; hydrogenated oils such as hydrogenated vegetable oil, 36°-37.5° C.;80% hydrogenated vegetable oil and 20% polysorbate 60, 36°-37° C.; 77.5%hydrogenated vegetable oil, 20% sorbitan trioleate and 2.5% beeswax,35°-36° C.; 72.5% hydrogenated vegetable oil, 20% sorbitan trioleate,2.5% beeswax and 5.0% distilled water, 37°-38° C.; mono-, di-, andtriglycerides of acids having from 8-22 carbon atoms including saturatedand unsaturated acids such as palmitic, stearic, oleic, lineolic,linolenic and archidonic; glycerides of fatty acids having a meltingpoint of at least 32° C. such as monoglycerides, diglycerides andtriglycerides of vegetable fatty acids having 11 to 18 carbon atoms,obtained from coconut oil, olive oil and the like; partiallyhydrogenated cottonseed oil, 35°-39° C.; hardened fatty alcohols andfats, 33°-36° C.; hexadienol and hydrous lanolin triethanolamineglyceryl monostearate, 38° C.; eutectic mixtures of mono-, di-, andtriglycerides, 35°-30° C.; Witepsol® W15, triglyceride of saturatedvegetable fatty acid with monoglycerides, 33.5°-35.5° C.; Witepsol® H32free of hydroxyl groups, 311°-33° C.; Witepsol® W25 having asaponification value of 225-240 and a melting poit of 33.5°-35.5° C.;Witepsol® E75 having a saponification value of 220-230 and a meltingpoint of 37°-39° C.; a polyalkylene glycol such as polyethylene glycol1000, a linear polymer of ethylene oxide, 38°-41° C.; polyethyleneglycol 1500, melting at 38°-41° C.; polyethylene glycolmonostearate,39°-42.5° C.; 33% polyethylene glycol 1500, 47% polyethylene glycol 6000and 20% distilled water, 39°-41° C.; 30% polyethylene glycol 1500, 40%polyethylene 4000 amd 30% polyethylene glycol 400, 33°-38° C.; mixtue ofmono-, di-, and tri-glycerides of saturated fatty acid having 11 to 17carbon atoms, 33°-35° C.; block polymer of 1,2-butylene oxide andethylene oxide; block polymer of propylene oxide and ethylene oxide;block polymer of polyoxyalkylene and propylene glycol, and the like. Thethermoresponsive composition is a means for storing a beneficial agentin a solid composition at a temperature of 20°-32° C., maintaining animmiscible boundary at the swelling composition at a temperature greaterthan 32° C., and preferably in the range of 32°-40° C. Thethermo-responsive composition on being dispensed into a biologicalenvironment are easily excreted, metabolized, assimilated, or the like,for effective use of the beneficial agent.

The dense member 20, also referred to as densifier 20, used in deliverysystem 10 is dense enough to retain system 10 in the rumen-reticular sacof a ruminant. Dense member 20 lets system 10 remain in the rumen over aprolonged period of time rather than letting it pass into the alimentarytract and be eliminated therefrom. As system 10 remains in the rumen,beneficial active agent 17 is delivered by system 10 at a controlledrate to the ruminant over time. Generally, dense member 20 will have adensity of from about 0.8 to 81, or higher, with the density in apresently preferred embodiment exhibiting a specific gravity of from 2.2to 7.6. For the ruminants, cattle and sheep, it is presently preferreddense member 20 exhibit a density such that there is a resulting systemdensity of about 3. Materials that have a density that can be used forforming dense member 20 include iron, iron shot, iron shot coated withiron oxide, iron shot magnesium alloy, steel, stainless steel, copperoxide, a mixture of cobalt oxide and iron powder, and the like. Densemember 20 in delivery system 10 can embrace different embodiments. Forexample, dense member 20 as seen in FIG. 2 is machined or cast as asingle, solid piece made of stainless steel having a density of 7.6. Thesolid member is made having a curved shape that corresponds to theinternal shape of system 10. The solid member has an axially alignedbore that extends through the length of the unit member. In anotherembodiment, dense member 20 can compose a pluralty of dense pellets. Inthis latter embodiment, the pellets are used as dense member 19 in FIG.3.

The term "beneficial agent" as used herein includes medicines or drugs,nutrients, vitamins, food supplements and other agents that benefit ananimal. The beneficial agent can be insoluble to very soluble in thetemperature sensitive material housed in the delivery system. The amountof agent present in a delivery system can be from 10 ng to 40 g or more.The delivery system can house various amounts of beneficial agent, forexample, 75 ng, 1 mg, 5 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1.5 mg, 2 g,5 g, 10 g, 25 g, and the like. A single delivery system can beadministered to a ruminant, or more than one delivery system can beadministered to a ruminant during a therapeutic program. Deliverysystems can be provided that have a rate of release from 5 micrograms to5 grams per day, or higher.

Representative of beneficial medicaments that can be dispensed using thedelivery system of this invention include anthelmintics such asbenzimidazole, mebendazole, levamisole, albendazole, cambendazole,fenbendazole, parbendazole, oxfendazole, oxygendazole, thiabendazole,tichlorfon, praziquantel, thiophanate, morantel, morantel tartrate,pyrantel, pyrantel tartrate, methoprene, and the like; antiparasiticagents for the management of endoparasites and ectoparasites, such asavermectin and ivermectin, as disclosed in U.S. Pat. Nos. 4,199,569 and4,389,397 both assigned to Merck & Co., and in Science, Vol. 221, pp823-828, 1983, wherein said ivermectin antiparasitic drug are disclosedas useful for aiding in controlling commonly occurring infestations inanimals, such as roundwords, lung worms and the like; and saidivermectin also being used for the management of insect infestationssuch as grub, lice, mange mite, mite, ticks, larve, flies such as larvewarble fly, dung-breeding fly, larve and flies in the excreta ofanimals; and the like, with delivery system administering from 5micrograms per kilogram per day (5 μg/kg/d), to 250 milligrams per day(250 mg/kg/d), to cattle for establishing avermectin, includingivermectin, blood levels; antimicrobial agents such aschloretetracycline, oxytetracycline, tetracycline, streptomycin,dihydrostreptomycin, bacitracins, erythromycin, chlortetracycline,ampicillins, penicillins, cephalosporins, and the like; sulfa drugs suchas sulfamethazine, sulfathiazole, sulfonamides, and the like; macrolidessuch as erythromycin, spiramycin, tylosin and the like; nitrofurans;antibiotics such as lasalocid, salinomycin and the like;growth-stimulants such as Monesin® sodium, and Elfazepam®; defleaingagents such as dexamthazone and flumethazone; rumen fermentationmanipulators; ironophores such as lasalocid, virginamycin and ronnel;antibloat agents such as organo-polysiloxanes; growth promoting agents;minerals, mineral salts and trace elements formulations such asmagnesium, copper, cobalt, iron, manganese, molybdenum, zinc, selenuim,copper oxide, copper sulfate, cobalt salt, copper salt, selenium salt,selenium disulfied, sodium selenite, inorganic, organic compounds,cobalt oxide, and the like; hormone growth supplements such asstilbestrol; growth efficiency factor, β-agonist such as lenbuterol;vaccines such as bovine diarrhea vaccine; vitamins such as vitamin A,B-group, C, D, E, K and the like; antienteritis agents such asfurazolidone; nutritional supplements such as lysine, lysinemonhydrochloride, methionine, mexhionine salts, amino acids, peptides,and the like; beneficial alpha agonists, and the like.

The semipermeable wall forming composition can be applied to theexterior surface of the capsule in laminar arrangement by molding, airspraying, dipping or brushing with a semipermeable wall formingcomposition. Other and presently preferred techniques that can be usedfor applying the semipermeable wall are the air suspension procedure andthe pan coating procedures. The air procedure consists in suspending andtumbling the capsule arrangement in a current of air and a semipermeablewall forming composition until the wall surrounds and coats the capsulemember. The procedure can be repeated with a different semipermeablewall forming composition to form a semipermeable laminated wall. The airsuspension procedure is described in U.S. Pat. No. 2,799,241; J. Am.Pharm. Assoc., Vol. 48, pp 451 to 459, 1979; and ibid, Vol. 49, pp 82 to84, 1960. Other standard manufacturing procedures are descirbed inModern Plastics Encyclopedia, Vol 46, pp 62 to 70, 1969; and inPharmaceutical Sciences, by Remington, 14th Edition, pp 1626 to 1678,1970, published by Mack Publishing Col, Easton, Pa.

Exemplary solvents suitable for manufacturing the semipermeable wallinclude inert inorganic and organic solvents that do not adversely harmthe materials, the capsule wall, the beneficial agent, thethermo-responsive composition, the expandable member, the dense member,and the final dispenser. The solvents broadly include members selectedfrom the group consisting of aqueous solvents, alcohols, ketones,esters, ethers, aliphatic hydrocarbons, halogenated solvents,cycloaliphatics, aromatics, heterocyclic solvents and mixtures thereof.Typical solvents include acetone, diacetone alcohol, methanol, ethanol,isopropyl alcohol, butyl alcohol, methyl isobutyl ketone, methyl propylketone, n-hexane, n-heptane, ethylene glycol monoethyl ether, ethyleneglycol monoethyl acetate, methylene dichloride, ethylene dichloride,propylene dichloride, carbon tetrachloride, nitroethane, nitropropane,tetrachlorethane, ethyl ether, isopropyl ether, cyclohexane,cyclooctane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran,diglyme, water, and mixtures thereof such as acetone and water, acetoneand methanol, acetone and ethyl alcohol, methylene dichloride andmethanol, and ethylene dichloride and methanol. Generally, for thepresent purpose the semipermeable wall is applied at a temperature a fewdegrees less than the melting point of the thermo-responsivecomposition. Or, the thermoplastic composition can be loaded into thedispenser after applying the semipermeable wall.

The expression, "means in the wall for releasing a beneficial agentformulation" includes at least one, or a plurality of preformed, orformed in the environment of use, orifices or passageways suitable forreleasing the beneficial agent formulation from the dispenser. The agentexit mean in the wall embraces also aperture; bore; pore; porouselement; hollow fiber; leachable element; dissolvable element; erodibleelement; hollow fiber; capillary tube; microporous member comprisingoverlay, insert, integral section, and the like; the agent exit meanscan be formed by mechanical drilling, by laser filling, by eroding anerodible element in the wall, by dissolving or leaching a pore formersuch as carbohydrate, and oxide a leachable material such as sorbitol,from a wall forming polymer composition thereby providing at least onepore of governed dimensions and porosity, and the like. The exitreleasing means can be a microporous insert or a microporous overlayformed during operation of the dispenser. the exit means can be presentin the wall formed in at least a part of a semipermeable material, orthe exit means can be through the semipermeable wall and the capsulewall. The exit means in one wall or both walls also can be formed bybursting or in response to pressure, especially when the dispenser is inoperation in the environment of use. A detailed description of orificesand passageways maximum and minimum dimensions is disclosed by Theeuwesand Higuchi in U.S. Pat. Nos. 3,845,770 and 3,916,899. A detaileddescription of an osmotically operated system with an agent releasingwall comprising and at least one pore, or a multiplicity of agentreleasing pores of regulated porosity formed by leaching and the like,is discussed by Ayer and Theeuwes in U.S. Pat. Nos. 4,200,098 and4,285,987. A dispenser of similar structure comprising a size-controlledporous releasing wall comprising a porous polymer and the pore formerhexanehexol or sorbitol is disclosed by Theeuwes in U.S. Pat. Nos.4,235,236; 4,309,996 and 4,320,759 for providing an osmotic dispenserwith pore releasing passageways.

DESCRIPTION OF EXAMPLES OF THE INVENTION

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those versed in the art in the light of the presentdisclosure, the drawings and the accompanying claims.

EXAMPLES

A delivery system manufactured in the shape of a dispenser for thecontrolled delivery of ivermectin is made as follows: first, 193 g ofButronic® L-1 polyol, a block polymer formed by the polymerization of1,2-butylene oxide to which ethylene oxide is added, as reported inCosmetics and Toiletries, Vol. 97, pp 61-66, 1982, which polymer flow ata pour point of 39° C., is melted at 55° C. and then 13.98 g ofivermectin is added thereto using a high sheer ultrasonic mixer. Theresulting mixture is placed in a vacuum oven at 55° and the pressurereduced to less than 10 mm of mercury. The ivermectin Butronic®composition is allowed to remain in the vacuum for a period of about 10minutes, for removing entrapped air. Next, 4 g of the resultingthermoplastic drug formulation is poured into a 1/2 oz gelatin capsulethat is previously charged with a 33 g stainless steel density memberhaving a bore therethrough. Then, an expandable driving membercomprising 2.1 g of sodium chloride and 4.9 g of the sodium salt ofpolyacrylic acid available as Carbopol® 934P is compressed into atablet. The tablet is formed using a 18.2 mm tableting tool and 31/2tons of compression force. The table has a final shape that correspondsto the internal shape of the opening of the capsule. The tablet memberthen is inserted into the opened end of the capsule until contact ismade with the drug polyol formation. Next, the capsule is coated in apan coater with a rate controlling wall comprising 1.8 g of 91%cellulose acetate butyrate and 9% polyethylene glycol 400. The wall iscoated from a 5% wt/wt solution in methylene chloride methanol 90:10 v/vsolvent system. The wall coated delivery systems then are dried at 30°C. for 24 hours. Next, a 30 mil exit passageway is drilled through thesemipermeable wall using a high speed mechanical drill for communicatingthe passageway with the bore. The passageway bore arrangementestablishes communication with the heat-responsive drug formulation fordelivering it from the delivery system. The dispenser made according tothis example has an average release rate of 0.5 mg per hour over a 480hr period of time.

EXAMPLE 2

A delivery system is made according to the procedure set forth inExample 1, with the conditions as set forth, except that in thisexample, the heat-responsive composition comprises 46.6 g of ivermectinand 200 g of polyethylene glycol 400 distearate, and theexpandable-swellable composition comprises 70% by weight ofpoly(ethylene oxide) having a molecular weight of 3,000,000 and 30% byweight of sodium chloride.

EXAMPLE 3

A dispenser system is prepared as follows: first, the body section of acapsule is positioned with its mouth in an upright position, and a densestainless steel element inserted into the hemispherical end of thecapsule. The dense element is machined and its shape matches theinternal shape of the capsule. Next, a layer of an exapandable-swellablecomposition is charged on top of the dense element. The compositioncomprises 25% by weight of sodium chloride and 75% by weight ofpoly(ethylene oxide) having a molecular weight of 2,000,000. Theexpandable forming ingredients are blended in a commercial blender withheat for 20 minutes to yield a homogeneous composition. The heatedcomposition is charged into the capsule forming a layer that occupiesabout 1/3 of the capsule. Next, a heat-sensitive drug formulationcomprising an eutectic mixture of 77% neutral fat having a melting pointof 35°-37° C. and 19.5% paraffin having a melting point of 52° C. isheated and 3.5% levamisole is added thereto. Then, the heated mixture iscooled to about 40° C. and injected into the capsule in contactingrelation with the expandable layer, and the capsule allowed to cool toroom temperature. Then, a solution of cellulose acetate, 15 wt %, withan acetyl content of 39.8%, is prepared in a methylene chloride methanolsolvent system and the capsule coated with a semi-permeable wall. Thewall is applied by dipping it into the coating solution for 15 times,first for a 5 second dip, then for two 10 seconds dips, then for a 30second dip and then for 1 minute per dip, with an intervening 5 minutedrying period. Following the dipping the delivery dispenser is dried atroom temperature, 72° F., about 22° C., for 5 days. The procedureapplies about a 2 mm thick semipermeable wall. A passageway is laserdrilled through the semipermeable wall connecting the exterior of thedispenser with the heat sensitive drug formulation for releasing it at acontrolled rate over time.

EXAMPLE 4

A dispensing system for delivering beneficial nutrients to warm-bloodedruminants is prepared as follows: first, a mold having a shape andconfiguration corresponding to the internal diameter and thehemispherical closed end of a capsule, is filled with an expandableforming composition comprising 30 parts of ethyleneglycolmonomethacrylate containing 0.12 parts of ethyleneglycol dimethacrylateand 10 parts of 0.13% aqueous solution of sodium disulfate in aqueousethanol. The composition polymerizes at 30° C., and after 20 minutesfollowing equilibrium to room temperature, the solid layer is removedfrom the mold. The solid expandable layer then is inserted, through themouth of the capsule into the hemispherical area of the capsule. Next, adense member made of stainless steel and machined in the shape of atablet is placed inside the capsule in contacting laminar arrangementwith the expandable layer. Next, the remainder of the capsule is filledwith a melted composition comprising 2.5% L-lysine HCl, 1.5%DL-methionine, 21% glycergelatin and 75% theobromo oil, a glyceride ofstearic acid, palmitic acid and lauric acid, to form on cooling to roomtemperature the thermo-responsive composition in laminar position withthe dense member. Next, the filled capsule is coated with a surroundingwall comprising cellulose acetate containing 10% polyethylene glycol400. The semipermeable wall is applied to a pan type Hi-coater. Thesolvent used for forming the wall consists essentially of methylenechloride and methanol 95 parts by weight to 5 parts by weight. A 12 mil(0.30 mm) thick wall of cellulose acetate butyrate is applied to theexterior surface of the capsule. Finally, a passageway is laser drilledthrough the semipermeable wall communicating with the heat-responsivenutrient containing composition for its delivery to the environment ofuse.

EXAMPLE 5

A delivery system is made according to the procedure set forth inExample 1, with the conditions and materials as set forth, except thatin this example a varying rate controlling wall thickness of celluloseacetate butyrate and polyethylene glycol 400 was applied to the system.The thickness of the rate controlling wall varied from 30 mil (0.76 mm)at the end distant from the passageway in a uniform taper to 15 mil(0.38 mm) adjacent to the density member. Accompanying FIG. 12 depictsthe amount of ivermectin antiparasitic released from the system over aprolonged period of 480 hours, and FIGS. 13 depicts the cumulativeamount of ivermectin released over the 480 hour period. The barsrepresent the minimum and maximum variation for the release rate of thetime of measurement.

EXAMPLE 6

A delivery system is made according to the procedure as set forth inExample 1, with all conditions and materials as previously described,except for the semipermeable wall that comprises 50% cellulose acetatebutyrate, 45% poly(sulfone) and 5% citroflex citric acid ester selectedfrom the group consisting of acetyl tributyl citrate and acetyltri-2-ethylhexyl citrate.

EXAMPLE 7

A delivery system is made according to the procedure as set forth inExample 1, with all conditions as described except that thesemipermeable wall comprises 80% cellulose acetate butyrate and 20%poly(sulfone), or 20% cellulose acetate butyrate and 80% poly(sulfone).

A presently preferred embodiment of the invention pertains to a methodof delivering a beneficial agent by formulating a heat-sensitivecomposition containing the beneficial agent and then delivering thebeneficial agent. An embodiment of the invention pertains also to amethod for administering a beneficial drug at a controlled rate to therumen of a ruminant, which method comprises the step of: (A) admittinginto rumen a dispensing device comprising: (1) an outer wall formed of asemipermeable polymeric composition permeable to the passage of fluidand substantially impermeable to the passage of drug, the wallsurrounding (2) an internal lumen containing a layer of a beneficialdrug formulation comprising a dosage unit amount of drug for preforminga therapeutic program in a heat-sensitive, pharmaceutically acceptablecarrier that melts at body temperature and is a means for transportingthe drug from the dispenser; (3) a layer of an expandable member in thelumen; (4) a layer of a dense member for maintaining the dispenser inthe rumen over a prolonged period of time; and (5) an orifice throughthe semipermeable wall communicating with the heat-sensitive drugformulation; (B) imbibing fluid through the semipermeable wall at a ratedetermined by the permeability of the semipermeable wall and the osmoticpressure gradient across the semipermeable wall causing the layer ofexpandable hydrogel to expand and swell; (C) melting the drugformulation to form a flowable formulation; and (D) delivering thebeneficial drug formulation from the compartment by the expandable layercontinually expanding against the melting formulation causing theformulation to be dispensed in a therapeutically effective amountthrough the orifice at a controlled rate to the rumen over a prolongedperiod of time.

The dispensing device provided by the invention are used, for example,for administering ivermectin to a warm-blooded animal at the rate of 5μg/kg/d to 250 μg/kg/d, and more, preferably at the rate of 10μg/kg/d/to 50 μg/kg/d for establishing plasma levels of about 2 ng/ml to100 ng/ml for substantially eliminating endoparasites in cattle, and forestablishing plasma levels of 10 ng/ml to 200 ng/ml for substantiallyeliminating ectoparasites in cattle. The accompanying FIG. 14 presentsmean steady state plasma levels as a function of dose rates. The solidline denotes the regression line based on the data. The hatched linesdenote the 95% confidence interval about the regression line. Thesquares, triangles, diamonds and horizontal-vertical intersecting linesindicate plasma measured points. The dispensing device providesprolonged administration of the medication to the animal accompanied bya reduction in the frequency of administration with the maintenance of arelatively constant drug concentration in the blood, leading to a moreuniform pharmacological response.

EXAMPLE 8

A dispensing device for the controlled delivery of the dietarysupplement selenium, present as sodium selenite, into the digestivetract of an animal is manufactured as followed: first, 5.7 kg ofcellulose acetate butyrate and 1.3 kg of cellulose acetate having anacetyl content of 39.8% are sizes then combined with 2.2 kg ofCitroflex®-4 tributyl citrate, 0.7 kg of Citroflex®-2 triethyl citrate,and 0.3 kg of polyethylene glycol 400, in the bowl of a large Hobart®mixer. After mixing for 20 minutes the blended material is transferredto the feed hoper of a Van Dorn injection molder, which is equipped witha suitable mold to produce 5.6 g cellulosic cup having the approximatedimensions 6.3 cm in height×2.1 cm in width and a wall thickness of 0.13cm.

Next, a 4.0 g of a hydrophilic expandable member comprising a 70:30ratio of sodium carboxymethylcellulose to sodium chloride, lubricatedwith 1% magnesium stearate, is compressed using 10,000 lbs of force in aCarver® laboratory press equipped with table tools and inserted into thecup.

Then, 300 g of Witco® Multiwax 180 M is combined with 300 g of Witco®Multiwax 145 and heated to 85° C. in an oven. The wax is delivered,approximately 2.9 ml, to the cup-hydrophilic assembly using a heatedsyringe.

The dietary supplement, sodium selenite formulation is prepared asfollows: 181 g of Witco Multiwax 180 M and 1,026 g of Witco Multiwax W835 are melted using a hot plate and the temperature adjusted toapproximately 68° C., then 213 g of sodium selenite is added to the waxblend and the mixture mixed using a high shear mixing apparatus. Whilemaintaining the temperature at 68° C., 6 ml aliquots of the melt aredelivered to individual cup assemblies and allowed to cool to roomtemperature.

Then, a sintered iron density element that possesses the dual functionof aiding the retention of the system in the rumen and serving as a flowmoderator is inserted into the open end of the dispenser and seatedagainst an internal stop. The protruding lip of the membrane cup isheated until softened using a hot air gun capable of delivering 600° F.air and the lip crimped over the density element.

EXAMPLE 9

The procedure of example 7 is repeated in this example with theconditions as previously set forth except that the present examplecomprises 1170 g of Witco® Multiwax W 835 food grade wax and 36 g ofcolloidal silicon dioxide to replace the 180 g of Multiwax 180 and the1,026 g Multiwax 835 of example 7, for the thermoresponsive carrier.

EXAMPLE 10

The procedure of example 7 is repeated in this example with the additionof 67:29:4 ratio of sodium Carbomer® polymer to sodium chloride topolyvinyl pyrrolidone lubricated with 1% magnesium stearate as areplacement for the sodium carboxymethylcellulose.

EXAMPLE 11

A dosage form for the controlled delivery of the anthelmintic ivermectinis manufactured as follows: first, 4.9 kg of cellulose acetate butyrateand 1.7 kg cellulose acetate having an acetyl content of 39.8% are sizedand then combined with 2.2 kg of tributyl citrate and 0.8 kg of triethylcitrate and 0.4 kg of polyethylene glycol in the bowl of a large mixer.After mixing for 20 minutes the material is transferred to the feedhoper of an injector molder equipped with a suitable mold to produce10.1 g cellulosic cup of the following dimensions: 7.9 cm in height, 2.5cm in width, and a wall thickness of 0.17 cm.

Next, 8.7 g of a blend comprising a 70:30 ratio of sodiumcarboxymethylcellulose to sodium chloride, lubricated with 1% magnesiumstearate, is compressed under 10 tons of force on a Stokes® bolus tabletpress. The compressed hydrophilic expandable member is inserted into thecups described above.

Then, 5.0 kg of Witco® Multiwax 180 M, a food grade wax, is combinedwith 5 kg Witco® Multiwax 145 and heated to 85° C. in a Slauterback® hotmelt tank-pump and 2.3 ml of the wax mixture delivered to the cup inlaminated arrangement to the hydrophilic member.

Then, a beneficial active agent ivermectin formulation is prepared asfollows: first 840 g of Witco® Multiwax 145 is melted using a hot plateand the temperature adjusted 80° C., then, 160 g of ivermectin is addedusing a high shear mixing apparatus. While keeping the temperature at68° C., aliquots comprising 11 ml of the melt are delivered toindividual cup assemblies and allowed to cool forming a lamina incontact with the lamina described above.

At this stage of the manufacture, about 40 mg to 80 mg of adhesive isplaced around the inside lip of the wall-cup assembly. Then, a sinterediron density member that has been preheated to 50° C. is inserted intothe open end of the wall-cup assembly and seated against the beneficialthermo-responsive beneficial agent formulation. Next, the protruding lipof the wall-cup is heated until softened using a hot air gun capable ofdelivering 600° F. air and the lip crimped over the density elementforming thereby an exit passageway.

EXAMPLE 12

The procedure of example 11 is repeated, with the conditions aspreviously described, except that the hydrophilic expandable membercomprises 67:29:4 ratio of sodium Carbomer® polymer, a polyacrylic acid,to sodium chloride to polyvinylpyrrolidone lubricated with 1% magnesiumstearate.

Inasmuch as the foregoing specification comprises preferred embodimentsof the invention, it is understood that variation and modifications maybe made herein in accordance with the inventive principles disclosed,without departing from the scope of the invention.

We claim:
 1. A method for producing an antiparasitic effect in an animalsuffering therewith, which method comprises:(a) admitting into theanimal a dosage form comprising:(1) a wall comprising cellulose acetatebutyrate and cellulose acetate, which wall defines an internal space;(2) a composition comprising a dosage unit amount of avermectin and atleast one wax for forming a dispensable formulation in the space; (3) acomposition comprising sodium carboxymethylcellulose and sodium chloridein the space; (4) a density member in the space, which density membermaintains the dosage form in the animal environment over a prolongedperiod of time; and, (5) at least one exit means in the dosage form fordelivering the avermectin; and, (b) administering the avermectin bycomposition (3) expanding in the space and exerting pressure against(2), whereby the avermectin is delivered through (5) to the animal forproducing the antiparasitic effect.
 2. The method for producing theantiparasitic effect according to claim 1, wherein the method treatsendoparasites.
 3. The method for producing the antiparasitic effectaccording to claim 1, wherein the method treats ectoparasites.
 4. Themethod for producing the antiparasitic effect according to claim 1,wherein the wall comprises tributyl citrate.
 5. The method for producingthe antiparasitic effect according to claim 1, wherein the wallcomprises triethyl citrate.
 6. The method for producing theantiparasitic effect according to claim 1, wherein the wall comprisestributyl citrate and triethyl citrate.
 7. The method for producing theantiparasitic effect according to claim 1, wherein the compositioncomprising avermectin comprises two food grade waxes.
 8. The method forproducing the antiparasitic effect according to claim 1, wherein theavermectin produces an antiparasitic effect for managing ticks.
 9. Themethod for producing the antiparasitic effect according to claim 1,wherein the avermectin is an ivermectin.
 10. A method for producing anantiparasitic effect in an animal suffering therewith, which methodcomprises:(a) admitting into the animal a dosage form comprising:(1) awall comprising cellulose acetate butyrate and cellulose acetate, whichwall defines an internal space; (2) a composition comprising a dosageunit amount of avermectin and at least one pharmaceutically acceptablewax for forming a dispensable formulation in the space; (3) acomposition comprising a carboxyvinyl polymer and an osmotic agent inthe space; (4) a density member in the space, which density membermaintains the dosage form in the animal environment over a prolongedperiod of time; and, (5) at least one exit means in the dosage form fordelivering the avermectin; and, (b) administering the avermectin bycomposition (3) expanding in the space and exerting pressure against(2), whereby the avermectin is delivered through (5) to the animal forproducing the antiparasitic effect.
 11. The method for producing anantiparasitic effect in an animal according to claim 10, wherein thecarboxyvinyl polymer is sodium carboxyvinyl polymer and the osmoticagent is sodium chloride.
 12. A method for producing an antiparasiticeffect in an animal suffering therewith, which method comprises:(a)admitting into the animal a dosage form comprising:(1) a wall comprisingcellulose acetate butyrate and cellulose acetate, which wall defines aninternal space; (2) an antiparasitic formulation in the space comprisinga beneficial amount of avermectin; (3) an expandable composition in thespace comprising sodium polyacrlic acid and sodium chloride; (4) adensity member in the space, which density member maintains the dosageform in the animal over a prolonged period of time; and, (5) at leastone exit means in the dosage form for releasing the avermectin; and, (b)administering the avermectin by the expandable composition expanding andurging the antiparasitic formulation through the exit means forproducing the antiparasitic effect.
 13. The method for producing theantiparasitic effect according to claim 12, wherein the method treatsendoparasites.
 14. The method for producing the antiparasitic effectaccording to claim 12, wherein the method treats ectoparasites.
 15. Themethod for producing the antiparasitic effect according to claim 12,wherein the wall comprises tributyl citrate.
 16. The method forproducing the antiparasitic effect according to claim 12, wherein thewall comprises triethyl citrate.
 17. The method for producing theantiparasitic effect according to claim 12, wherein the wall comprisestributyl citrate and triethyl citrate.
 18. The method for producing theantiparasitic effect according to claim 12, wherein the compositioncomprising avermectin comprises two pharmaceutically acceptable foodgrade waxes.
 19. The method for producing the antiparasitic effectaccording to claim 12, wherein the avermectin produces an antiparasiticeffect for managing ticks.
 20. The method for producing theantiparasitic effect according to claim 12, wherein the avermectin is anivermectin.
 21. A method for administering selenium to an animal, whichmethod comprises:(a) admitting into the animal a dosage formcomprising:(1) a wall comprising cellulose acetate butyrate andcellulose acetate, which wall defines an internal space; (2) acomposition comprising a beneficial amount of selenium and at least onewax carrier in the space; (3) a composition comprising sodiumcarboxymethylcellulose and sodium chloride in the space; (4) a densitymember in the space, which density member maintains the dosage form inthe animal over a prolonged period of time; and, (5) at least one dosagemeans in the dosage form for delivering the selenium; and, (b)administering the selenium to the animal by composition (3) expandingand exerting pressure against composition (2), whereby selenium isdelivered through (5) to the animal over a prolonged period of time. 22.The method for administering selenium to the animal according to claim21, wherein the wall comprises tributyl citrate.
 23. The method foradministering selenium to the animal according to claim 21, wherein thewall comprises triethyl citrate.
 24. The method for administeringselenium to the animal according to claim 21, wherein the selenium issodium selenite.
 25. The method for administering selenium to the animalaccording to claim 21, wherein the composition comprising sleniumcomprises two different waxes.
 26. A method for administering seleniumto an animal, which selenium method comprises:(a) admitting into theanimal a dosage form comprising:(1) a wall comprising cellulose acetatebutyrate and cellulose acetate, which wall defines an internal space;(2) a composition comprising a beneficial amount of selenium and atleast one nontoxic wax carrier in the space; (3) an expandablecomposition in the space comprising sodium polyacrylic acid and sodiumchloride; (4) a density member in the space, which density membermaintains the dosage form in the animal over a prolonged period of time;and, (5) at least one exit means in the dosage form for releasing theselenium; and, (b) administering the selenium by the expandablecomposition expanding and urging the selenium through the exit means foradministering it to the animal.
 27. A method for establishing a bloodlevel of avermectin in an animal in need of avermectin for themanagement of an infestation, which method comprises: introducing intothe rumen of the animal a dosage form, which dosage form comprises awall that surrounds and defines an internal lumen; a dosage amount ofavermectin in the lumin; a pharmaceutically acceptable lipophiliccarrier for avermectin in the lumin; and means for delivering saidavermectin from the dosage form to the rumen of the animal at acontrolled rate over a prolonged period of time for establishing theblood level of avermectin in said animal.
 28. A method for thecontrolled release of trace elements in the digestive tract of an animalin need of a trace element, which method comprises; introducing into thedigestive tract of the animal a dosage form, which dosage form comprisea wall that surrounds and defines a lumen; a dosage amount of a traceelement in the lumen; a pharmaceutically acceptable lipophilic carrierfor trace elements in the lumen; and means in the dosage form fordelivering said trace element into the digestive tract at a controlledrate over a prolonged period of time.
 29. A method for producing a bloodlevel of invermectin in a ruminant in need of invermectin for themanagement of an infestation, which method comprises: admitting into theruminant a delivery device comprising a wall that surrounds and forms aninternal compartment; a dosage amount of invermectin of the compartment;a pharmaceutically acceptable lipophilic carrier for invermectin in thecompartment; means in the delivery device for delivering the ivermectinfrom the delivery device; and which delivery device administers theivermectin to the ruminant at a controlled rate over a prolonged periodof time for producing the blood level of ivermectin in the ruminant. 30.A method for producing a growth promotion effect in a warm-bloodedanimal by treating endo and ectoparasites in an animal afflicted withsame, which method comprises:(a) admitting into the animal a dosage formcomprising:(1) a wall comprising cellulose formulation, which walldefines an internal space; (2) a beneficial formulation in the spacecomprising an effective amount of avermectin; (3) an expandablecomposition in the space comprising a polyacrylic acid; (4) a densitymember in the space, which density member maintains the dosage form inthe animal over a prolonged period of time; and, (5) at least one exitmeans in the dosage form for releasing the avermectin; and, (b)administering the avermectin by the expandable composition expanding andurging the beneficial formulation through the exit means for treatingthe endo and ectoparasites thereby producing a growth promotion effect.31. A method for producing a growth promotion effect in a warm-bloodedanimal by treating endo and ectoparasites in an animal suffering withsame, which method comprises:(a) admitting into the animal a dosage formcomprising:(1) a wall comprising cellulose formulation, which walldefines an internal space; (2) a composition comprising a dosage unitamount of avermectin in at least one pharmaceutically acceptable carrierfor forming a dispensable formulation in the space; (3) a compositioncomprising carboxymethylcellulose in the space; (4) a density member inthe space, which density member maintains the dosage form in the animalenvironment over a prolonged period of time; and, (5) at least one exitmeans in the dosage form for delivering the avermectin; and, (b)administering the avermectin by the composition comprisingcarboxymethylcellulose expanding and urging the avermectin through theexit means for treating the endo and ectoparasites thereby producing agrowth promotion effect.